Relapse to cocaine use following prolonged abstinence is a significant impediment in the treatment of cocaine dependence. Several risk factors have been recognized as critical in triggering relapse to drug-seeking and drug-taking behavior in cocaine-dependent individuals. Human laboratory studies indicate that either cocaine-related cues or negative emotional stimuli can produce craving and physiological arousal. Likewise, animal models of relapse (e.g., the reinstatement of operant drug-seeking behavior) have clearly demonstrated that conditioned cues or exposure to acute stress elicits reinstatement of cocaine-seeking behavior in animals with a history of cocaine self-administration. These two risk factors, cues and stress, have been increasingly studied in regards to their ability to promote drug-seeking behavior and they represent the two best targets for relapse medication development. However, there has been minimal consideration of the interaction of these trigger factors in relapse, and almost no attempts to implement a translational approach to the empirical study of relapse and relapse prevention within a unified project. This proposed project will establish an interdisciplinary approach to study the primary risk factors for relapse (stress and cues) by using both an animal model of relapse and an established human clinical laboratory setting for assessing drug craving. In the animal model, acute stress exposure (foot shock stress or social stress) will be examined for the potentiative effects of stress on conditioned-cue (tone+light) responding on a previously cocaine-paired lever. In addition, we will test the effects of a novel dopamine partial agonist (aripiprazole) and a glutamate enhancing agent (modafinil) on stress, cue, and stress+cue induced reinstatement. In close parallel to the reinstatement experiments, we will directly assess stress, cue, and stress+cue interactions in a clinical laboratory setting. Specifically, HPA axis (ACTH, cortisol), physiological (heart rate, blood pressure, skin conductance), and subjective responses to acute stress (Trier Social Stress Test) or no stress followed by cocaine-related cue reactivity (self-reported drug craving) will be determined in cocaine-dependent individuals. As in the reinstatement model experiments, subjects will receive aripiprazole, modafinil, or placebo control prior to testing for stress and cue reactivity. In both the animal model and the human laboratory, we predict that stress exposure will potentiate responding to cocaine-paired cues and that craving and relapse will be attenuated by aripiprazole or modafinil. In summary, this project will: a) provide a unique interdisciplinary approach to bridge the gap between an established animal model of relapse with a clinical laboratory paradigm that will directly test the interaction of stress and cues in relapse, and b) simultaneously assess putative pharmacotherapies in both the animal model and the human laboratory for the treatment of cocaine addiction.